PROJECT SUMMARY Heart disease is the leading cause of mortality and morbidity in the world. Coronary heart disease is the most common type of heart disease and results from the blockage of blood vessels that supply blood to the heart. A heart attack or myocardial infarction (MI) occurs when loss of blood flow causes the death of oxygen- starved cardiomyocytes. In humans, there is little or no significant cardiac muscle regeneration after an injury like a heart attack. Instead, dead cardiomyocytes are replaced by nonfunctional scar tissue, which weakens the heart and can lead ultimately to heart failure and death. Current therapies for heart attack are limited to reducing post-MI heart damage, preventing secondary heart attacks and treating resultant heart failure. Development of therapies that stimulate regeneration of the heart is a strategic priority for the National Heart Lung and Blood Institute. While under intensive study, no such therapies currently exist. MSI-1436 is potent and specific inhibitor of the tyrosine phosphatase PTP1B. PTP1B inactivates diverse receptor tyrosine kinases that regulate innate tissue repair and regeneration processes. Using blinded and randomized experimental and data analysis protocols, we have shown that MSI-1436 stimulates regeneration of adult zebrafish heart, connective, nerve, skin, bone and vascular tissues after amputation, and reverses genetically induced cardiac scar formation. In adult mice, MSI-1436 stimulates stem celI activation in injured skeletal muscle and increases survival, improves heart function ~2-fold, reduces infarct size by 53% and stimulates cellular proliferation 4.5-fold at 4 weeks post-MI. MSI-1436 was previously shown to be well tolerated by patients in Phase 1 and 1b clinical trials as a potential treatment for obesity and type-2 diabetes. The effects of MSI-1436 on regeneration occur at concentrations 50-fold lower than the maximum well tolerated human dose. The demonstrated safety of MSI-1436 and extensive knowledge of its target greatly reduce the time and costs associated with developing this drug as a regenerative medicine therapy for treating acute MI. We will test the efficacy of MSI-1436 in the restoration of heart function in a clinically relevant pig ischemia/reperfusion MI model. Porcine models have become the standard large animal system for studies of cardiac function due to similarities in heart morphology and metabolism to humans. Cardiac function will be measured by echocardiography and infarct size, cardiomyocyte regeneration and cardiomyocyte hypertrophy will be assessed by histology. Testing the efficacy of MSI-1436 in the pig is the required next step towards potential clinical trials. As with all our previous work, proposed pig studies will be blinded and randomized and will be performed in collaboration with lead investigators of the NIH/NHLBI sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR). Demonstrated efficacy in the pig will form an essential component of an FDA IND application for MSI-1436 clinical trials in MI patients.